JP2594420B2 - Substituted diphenylethylene derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a substituted diphenylethylene derivative having excellent action as a medicament, a pharmaceutically acceptable salt thereof, a method for producing the same, and a medicament containing the same.

[0002]

2. Description of the Related Art At present, one of the serious health risks for human beings is acute vascular disease such as myocardial infarction, stroke, cerebral thrombosis, cerebral infarction, pulmonary embolism, deep vein thrombosis, peripheral artery. Obstruction and the like. In recent years, antiplatelet agents have attracted clinical attention and are being widely used as one of the therapeutic agents for these diseases, but the history of antiplatelet agents is relatively new, and the development of better drugs is expected in the future. I have.

[0003]

An object of the present invention is to provide a substituted diphenylethylene derivative having excellent action as a pharmaceutical and a pharmacologically acceptable salt thereof, and further provide the substituted diphenylethylene derivative and a pharmacologically acceptable salt thereof. It is an object of the present invention to provide a method for producing a salt which is acceptable to the public, and to provide a medicament comprising the substituted diphenylethylene derivative and a pharmaceutically acceptable salt thereof as an active ingredient.

[0004]

The object compound of the present invention is a substituted diphenylethylene derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0005]

Embedded image

In the formula, R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups. X represents a cyano group. Y is the formula -Alk-COOR ³ (where Alk is
Formula - (CH _{2) n} - refers to the group or branched alkylene group represented by (n is an integer of 1 to 3 in the formula), R ³
Represents a hydrogen atom or a lower alkyl group]. Provided that R ¹ , R ² and R ³ are hydrogen atoms and n =
In the case of 1, and R ¹ and R ² are the same or different hydroxyl groups or lower alkoxy groups and Alk is

[0007]

Embedded image

[0008] Except for the case of a group represented byに お い て In the above definition, a lower alkyl group found in R ³ is a linear or branched alkyl group having 1 to 6 carbon atoms,
For example, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-
Butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl, etc., and the lower alkoxy group found in R ¹ and R ² means all lower alkoxy groups derived from the above lower alkyl groups. I do. Of these, the most preferred are a methyl group and an ethyl group for a lower alkyl group, and a methoxy group for a lower alkoxy group.

In the definition of Y, when Alk represents a group represented by the formula-(CH ₂ ) _n- , n represents an integer of 1 to 3. Also,
A branched alkylene group preferably has 1 to 1 carbon atoms.
In the alkylene group 3, it means that a lower alkyl group such as a methyl group or an ethyl group is bonded to any carbon atom. A good example would be

[0010]

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In the present invention, pharmacologically acceptable salts include, when R ³ is a hydrogen atom in the structural formula of the target substance, for example, metal salts such as Na, K, Ca, and Mg.

[0012] Although are various method for producing the manufacturing method of the present invention compound (I), it is as follows Stated representative methods of these.

[0013]

Embedded image

That is, a ketone body represented by the general formula (II):
The halogenated compound represented by the general formula (III) is reacted by a conventional method in a tetrahydrofuran solvent in the presence of, for example, zinc to obtain a hydroxy compound (IV) (Reformatsky reaction). As the solvent, for example, tetrahydrofuran, benzene, ether and the like can be used, but if necessary, the reaction can be carried out in a mixed solvent with trimethyl borate, triethyl borate and the like. This reaction is usually carried out at about -70.
Performed at a temperature of ~ 150 ° C.

From the obtained hydroxy compound (IV), the desired compound (V) can be obtained by a usual dehydration method. In this reaction, benzene, toluene,
Tetrahydrofuran, ether, dioxane and the like can be used, and as a catalyst, p-toluenesulfonic acid, thionyl chloride, phosphorus pentoxide, iodine, hydrochloric acid and the like can be used.
The reaction temperature is about -70 to 150 ° C.

Here, Y is a group represented by the formula-(CH ₂ ) _n -COOR ³ (wherein n and R
³ has the meaning described above).
The details are as follows.

[0017]

Embedded image

Next, representative compounds of the present invention will be listed, but the purpose is to make the present invention easier to understand, and it is meant that the scope of the present invention is not limited thereby. Not even. In addition, all the following descriptions are described in a free form.

3-ethyl cyano-4,4-bis (4-methoxyphenyl) -3-butenoic acid ethyl ester 3-cyano-4,4-bis (4-ethoxyphenyl)-
3-butenoic acid ethyl ester • 3-cyano-4,4-bis (4-hydroxyphenyl)
-3-butenoic acid ethyl ester • 3-cyano-4- (4-methoxyphenyl) -4-
(4-ethoxyphenyl) -3-butenoic acid ethyl ester • 3-cyano-4,4-bis (4-methoxyphenyl)-
3-butenoic acid 3-cyano-4,4-bis (4-ethoxyphenyl)-
3-butenoic acid 3-cyano-4,4-bis (4-hydroxyphenyl)
-3-butenoic acid 3-cyano-4- (4-methoxyphenyl) -4-
(4-ethoxyphenyl) -3-butenoic acid-5-cyano-6,6-bis (4-methoxyphenyl)-
5-hexenoic acid methyl ester • 5-cyano-6,6-bis (4-ethoxyphenyl)-
5-hexenoic acid methyl ester • 5-cyano-6,6-bis (4-hydroxyphenyl)
-5-Hexenoic acid methyl ester -5-cyano-6- (4-methoxyphenyl) -6
(4-ethoxyphenyl) -5-hexenoic acid methyl ester • 5-cyano-6,6-bis (4-methoxyphenyl)-
5-hexenoic acid 5-cyano-6,6-bis (4-ethoxyphenyl)-
5-hexenoic acid 5-cyano-6,6-bis (4-hydroxyphenyl)
-5-hexenoic acid 5-cyano-6- (4-methoxyphenyl) -6
(4-ethoxyphenyl) -5-hexenoic acid.

The substituted diphenylethylene derivative provided by the present invention has an excellent platelet aggregation inhibitory action,
It is useful as a therapeutic agent based on this action, that is, as an antiplatelet agent and an antithrombotic agent. Specifically, cerebrovascular disorders such as TLA (transient cerebral ischemic attack), cerebral infarction (thrombosis, embolism), cerebral arteriosclerosis, thrombus and emboli after vascular surgery and postoperative blood associated with extracorporeal blood circulation, and blood Treatment and prevention of chronic arterial occlusive disease such as blood flow disorder, Buerger's disease, obstructive arteriosclerosis, peripheral arteriosclerosis, SLE, leukoderma, angina pectoris, myocardial infarction, etc. It is useful for preventing recurrence of the disease and improving prognosis.

Next, pharmacological experimental examples will be given in order to explain the effects of the compounds of the present invention in detail. Experimental Example 1. Platelet aggregation inhibitory action (in vitro) Blood was collected from human elbow vein so as to contain a 1/10 volume of 3.8% sodium citrate solution [Packham, M .;
126 , 171-189 (1967)], platelet floating plasma (PRP... Platelet Rich Plasma) was prepared. Various concentrations of Compounds A to
C, 25 μl of the solution was added, and the mixture was incubated at 37 ° C. for 3 minutes to induce platelet aggregation with arachidonic acid, collagen, ADP and PAF. Platelet aggregation was performed using Aggregometor from Schenko or Nikko Biosciences.
Using the method of Mustard et al. [Mustard, JF, et al, J.
LabClin. Med. 64 , 548-559 (1964)]. Table 1 shows the results.

[0022]

[Table 1]

In Table 1 above, Compound A is the target substance obtained in Example 1, and Compounds B and C are Reference Examples 1 and 2.
Means the compounds obtained in the above.

2. Platelet aggregation inhibitory action (ex vivo) Compounds A to C were orally administered to guinea pigs, and after 2 hours, blood was collected from abdominal aorta under ether anesthesia, collagen (3 μg / ml) and arachidonic acid (50 μM) The platelet aggregation inhibitory effect of was investigated. The solvent administration rate was determined, and the 50% effective dose is shown in Table 2.

[0025]

[Table 2]

3. Acute toxicity Rats (body weight) were used for a representative compound of the present invention (compound A) and compounds B and C obtained in Reference Examples 1 and 2.
When an acute toxicity test was performed using a 300 to 400 g Wistar system (II), the LD ₅₀ was 500 mg / kg or more in all cases.

When the compound of the present invention is used as an antiplatelet agent or an antithrombotic agent, it is administered orally or parenterally (intramuscularly, subcutaneously, intravenously, etc.). The dose is
It varies according to the difference of disease, degree of symptoms, age, etc., and is not particularly limited. In the case of an adult, it is usually 0.1 to 300 m per day.
g, preferably 0.1-60 mg, more preferably 0.3-30 m
g, more preferably 0.6 to 10 mg.

In order to formulate the compound of the present invention, tablets, granules, powders, capsules, injections, suppositories and the like are prepared in a usual manner in the technical field of formulation. That is,
When an oral solid preparation is manufactured, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, and the like are added to the main drug, if necessary, and then tablets, coated tablets, and the like are obtained in a conventional manner. Granules, powders, capsules, etc.

As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, etc., and as binders, for example, polyvinyl alcohol,
Polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. Sodium, calcium citrate, dextrin, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., and as coloring agents, those which are allowed to be added to pharmaceuticals However, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder and the like are used as flavoring agents. These tablets and granules can of course be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjusting agent, a buffer, a stabilizing agent, a preservative and the like are added to the main drug, if necessary, to give a subcutaneous, intramuscular, or intravenous injection according to a conventional method.

[0031]

EXAMPLES Next, reference examples and examples of the present invention will be described. However, it goes without saying that the present invention is not limited to these examples.

Reference Example 1 4-cyano-5,5-bis (4-methoxyphenyl) -4
- In pentenoic acid ethyl ester [Formula (I), X = CN, Y = - (CH 2) 2 -COOC
₂ H _5] 4,4'-dimethoxy benzophenone 2.42 g (0.01 mol), zinc 1g, trimethyl borate 2.1 g, was suspended in tetrahydrofuran 15 ml, which then 4-bromo-4-cyano butyric acid ethyl ester 2.2g and A catalytic amount of iodine is added and reacted at room temperature for 5 hours. After completion of the reaction, 10 ml of a saturated aqueous ammonium chloride solution was added, and after stirring for 1 hour, zinc was removed by filtration and the filtrate was extracted with ethyl acetate. The crude product was purified by silica gel chromatography to give 1.5 g of white crystals.
Get. This was dissolved in benzene (10 ml), thionyl chloride (1 ml) was added, and the mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and dispersed in ice water. Then, it was extracted with benzene, washed with water and concentrated. Then, the residue was purified by silica gel column chromatography to obtain 1.3 g of the title compound as a colorless oil.

NMR (CDCl ₃ ) δ: 6.7 to 7.3 (8H), 4.1 (2H),
3.8 (6H), 2.7 (4H), 1.3 (3H) Reference Example 2 4-cyano-5,5-bis (4-methoxyphenyl) -4
- [In formula (I), X = CN, Y = - (CH 2) 2 -COOH ] pentenoic acid 4-cyano-5,5 - bis (4-methoxyphenyl) -4
-3.6 g of pentenoic acid ethyl ester was dissolved in 10 ml of dioxane, and 3 ml of 5N NaOH aqueous solution was added thereto.
Stir at C for 5 hours. After the reaction is completed, the reaction solution is made acidic,
Extract with ethyl acetate to give the title compound having the following physical properties
3.2 g are obtained. This can be further recrystallized and purified with ethyl acetate-hexane.

Melting point (° C.): 124 to 125 NMR (CDCl ₃ ) δ: 9.5 (1H), 6.8 to 7.4 (8H), 3.8 (6H), 2.
7 (4H) Example 1 5-cyano-6,6-bis (4-methoxyphenyl) -5
- [In formula (I), X = CN, Y = - (CH 2) 3 -COOCH 3 ] hexenoic acid methyl ester instead of 4-bromo-4-cyano-butyric acid ethyl ester
The same treatment as in Reference Example 1 was performed using 2.2 g of methyl 5-bromo-5-cyanopentanoate to give the title compound having the following physical properties.

NMR (CDCl ₃ ) δ: 6.7 to 7.3 (8H), 3.8 (6H),
3.6 (3H), 1.8-2.6 (6H) Example 2 5-cyano-6,6-bis (4-methoxyphenyl) -5
- [In formula (I), X = CN, Y = - (CH 2) 3 -COOH ] hexenoic acid obtained in Example 1 5-Cyano-6,6 - bis (4-methoxyphenyl) -5- Hexenoic acid methyl ester 260mg
Was treated in the same manner as in Reference Example 2 to obtain 250 mg of the title compound.

NMR (CDCl ₃ ) δ: 8.0 to 9.0 (1H), 7.1 to 7.3
(2H), 6.7 ~ 7.0 (6H), 3.8 (6H), 2.2 ~ 2.5 (4H), 1.8 ~
2.2 (2H)

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Koji Nakamoto, Inventor 712-91 Nakanuki, Tsukiura-shi, Ibaraki Pref. (72) Kazuo Okano 4-19-13, Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Eisai Mt. Person Shinya Abe 1083-44, Meka-cho, Ushiku City, Ibaraki Prefecture (72) Inventor Hironori Ikuta 2-35-12, Sakae-cho, Ushiku City, Ibaraki Prefecture (72) Inventor Kenji Hayashi 3-7-1, Ninomiya, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture ( 72) Inventor Hiroyuki Yoshimura 4-19-13, Kasuga, Yatabe-cho, Tsukuba-gun, Ibaraki Pref.Eisai Shizan Ryo (72) Inventor Toru Fujimori 2-9-9 Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki Pref. (72) Inventor Kokichi Harada, Ibaraki 4-19-13 Kasuga, Yatabe-cho, Tsukuba-gun Eisai Shizan Ryo (72) Inventor Isao Yamatsu 3605-669, Kashiwada-cho, Ushiku-shi, Ibaraki Pref. (56) References ARZNEIM. -FORSCH37 (10), 1143-8, 1987 BULL. SOC. CHIM. FR. (12), 3895-900, 1966

Claims (8)

(57) [Claims] 1. A substituted diphenylethylene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image In the formula, R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups. X represents a cyano group. Y is a group represented by the formula -Alk-COOR ³ (where Alk is a group represented by the formula-(CH ₂ ) _n-
(Wherein n represents an integer of 1 to 3) or a branched alkylene group, and R ³ represents a hydrogen atom or a lower alkyl group.] However, when R ¹ , R ² and R ³ are hydrogen atoms and n = 1, and R ¹ and R ² are the same or different hydroxyl groups or lower alkoxy groups and Alk is Except when it is a group represented by ｝ 2. The substituted diphenylethylene derivative according to claim 1, wherein R ¹ and R ² are both lower alkoxy groups, or a pharmaceutically acceptable salt thereof. 3. The substituted diphenylethylene derivative according to claim 1, wherein R ¹ and R ² are both methoxy groups, or a pharmaceutically acceptable salt thereof. 4. A method according to claim 1, wherein Y is of the formula-(CH ₂ ) _n -COOR ³ , wherein n and R ³
The substituted diphenylethylene derivative according to claim 1, or a pharmacologically acceptable salt thereof. 5. A group wherein R ¹ and R ² are both lower alkoxy groups, and Y is a group represented by the formula — (CH ₂ ) _n —COOR ³ (wherein n and R ³ have the same meanings as above). The substituted diphenylethylene derivative according to claim 1, or a pharmaceutically acceptable salt thereof. 6. The substituted diphenylethylene derivative according to claim 5, wherein R ¹ and R ² are both methoxy groups, or a pharmaceutically acceptable salt thereof. 7. The method according to claim 1, wherein the compound is 5-cyano-6,6-bis- (4
The substituted diphenylethylene derivative according to claim 1, which is -methoxyphenyl) -5-hexenoic acid methyl ester, or a pharmaceutically acceptable salt thereof. 8. A compound of the general formula (I) In the formula, R ¹ and R ² represent the same or different hydrogen atoms, hydroxyl groups or lower alkoxy groups. X represents a cyano group. Y is a group represented by the formula -Alk-COOR ³ (where Alk is a group represented by the formula-(CH ₂ ) _n-
(Wherein n represents an integer of 1 to 3) or a branched alkylene group, and R ³ represents a hydrogen atom or a lower alkyl group.] However, when R ¹ , R ² and R ³ are hydrogen atoms and n = 1, and when R ¹ and R ² are the same or different hydroxyl groups or lower alkoxy groups and Alk is Except when it is a group represented by An antiplatelet / antithrombotic agent comprising a substituted diphenylethylene derivative represented by｝ or a pharmacologically acceptable salt thereof as an active ingredient.